extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. The ECD contains the ligand binding sites for these receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  45 KHEDSLFRDLFEDYERWVRPVEHLSDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVP 124
Cdd:cd19018    1 KSEDRLFKHLFQDYQRWVRPVEHLNDTIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYAGITSIRVP 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 125 SDSLWIPDIVLFDNADGRFEGASTKTVVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILED 204
Cdd:cd19018   81 SDSIWIPDIVLYDNADGRFEGTSTKTVVRYDGTITWTPPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILED 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 158534079 205 QDVDRTDFFDNGEWEIMSAMGSKGNRTDSCCWYPYITYSFVIKRLPL 251
Cdd:cd19018  161 YDVDKRDFFDNGEWEIVSATGSKGNRTDGCCWYPFITYSFIIRRLPL 207

extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (alpha5), encoded by the CHRNA5 gene, which is part of the CHRNA5/A3/B4 gene cluster. Polymorphisms in this gene cluster have been identified as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. A loss-of-function polymorphism in CHRNA5 is strongly linked to nicotine abuse and schizophrenia; the alpha5 nAChR subunit is strategically situated in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. Alpha5 forms heteropentamers with alpha3beta2 or alpha3beta4 nAChRs which increases the calcium permeability of the resulting receptors possibly playing significant roles in the initiation of ACh-induced signaling cascades under normal and pathological condition. Acetylcholine (ACh) release and signaling via alpha4/beta2 nAChR subunits plays a central role in the control of attention, but a subset of these oligomers also contains alpha5 subunit. A strong association is seen between a CHRNA5 polymorphism and the risk of lung cancer, especially in smokers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  45 KHEDSLFRDLFEDYERWVRPVEHLSDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVP 124
Cdd:cd19018    1 KSEDRLFKHLFQDYQRWVRPVEHLNDTIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYAGITSIRVP 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 125 SDSLWIPDIVLFDNADGRFEGASTKTVVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILED 204
Cdd:cd19018   81 SDSIWIPDIVLYDNADGRFEGTSTKTVVRYDGTITWTPPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILED 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 158534079 205 QDVDRTDFFDNGEWEIMSAMGSKGNRTDSCCWYPYITYSFVIKRLPL 251
Cdd:cd19018  161 YDVDKRDFFDNGEWEIVSATGSKGNRTDGCCWYPFITYSFIIRRLPL 207

Neurotransmitter-gated ion-channel ligand binding domain; This family is the extracellular ligand binding domain of these ion channels. This domain forms a pentameric arrangement in the known structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079   47 EDSLFRDLFEDYERWVRPVEHLSDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSD 126
Cdd:pfam02931   1 EERLLDDLLSGYDKLVRPVANGSDPVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNPEDYGGITSLRLPSD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  127 SLWIPDIVLFDNADGRFEGA--STKTVVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILED 204
Cdd:pfam02931  81 KIWKPDIVLYNKADGIHEVTtpNTNVRVYYDGTVLWSPPAIYKSSCSIDVTYFPFDEQNCSLKFGSWTYNGEEVDLRWDD 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 158534079  205 QD-------VDRTDFFDNGEWEIMSAMGSKG-NRTDSCCW-YPYITYSFVIKRLP 250
Cdd:pfam02931 161 DPpvveleeIDLSDFWLNGEWDIVDVPAKRReYPYGCYSElTGDVTFYFTLRRKP 215

transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 251 LFYTLFLIIPCIGLSFLTVVVFYLPSNEGEKISLCTSVLVSLTVFLLVIEEIIPSSSKVIPLIGEYLVFTMIFVTLSIMV 330
Cdd:cd19064    1 LFYTVNLIIPCVLISFLTVLVFYLPADSGEKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSIIV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 331 TVFAINIHHRsssthnamapwvrkiflhklpkllcmrshadryftqreeaesgagpksrntleaaldciryitrhvvken 410
Cdd:cd19064   81 TVIVLNVHHR---------------------------------------------------------------------- 90

                        170       180       190
                 ....*....|....*....|....*....|....*..
gi 158534079 411 dvrevvedwkfiaqVLDRMFLWTFLLVSIIGTLGLFV 447
Cdd:cd19064   91 --------------VIDRLFLWIFLLVCVIGTLGIFL 113

extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (alpha5), encoded by the CHRNA5 gene, which is part of the CHRNA5/A3/B4 gene cluster. Polymorphisms in this gene cluster have been identified as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. A loss-of-function polymorphism in CHRNA5 is strongly linked to nicotine abuse and schizophrenia; the alpha5 nAChR subunit is strategically situated in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. Alpha5 forms heteropentamers with alpha3beta2 or alpha3beta4 nAChRs which increases the calcium permeability of the resulting receptors possibly playing significant roles in the initiation of ACh-induced signaling cascades under normal and pathological condition. Acetylcholine (ACh) release and signaling via alpha4/beta2 nAChR subunits plays a central role in the control of attention, but a subset of these oligomers also contains alpha5 subunit. A strong association is seen between a CHRNA5 polymorphism and the risk of lung cancer, especially in smokers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  45 KHEDSLFRDLFEDYERWVRPVEHLSDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVP 124
Cdd:cd19018    1 KSEDRLFKHLFQDYQRWVRPVEHLNDTIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYAGITSIRVP 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 125 SDSLWIPDIVLFDNADGRFEGASTKTVVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILED 204
Cdd:cd19018   81 SDSIWIPDIVLYDNADGRFEGTSTKTVVRYDGTITWTPPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILED 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 158534079 205 QDVDRTDFFDNGEWEIMSAMGSKGNRTDSCCWYPYITYSFVIKRLPL 251
Cdd:cd19018  161 YDVDKRDFFDNGEWEIVSATGSKGNRTDGCCWYPFITYSFIIRRLPL 207

extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (CHRNB3); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (beta3), encoded by the CHRNB3 gene. CHRNB3 polymorphisms have been reported to potentially affect nicotine-induced upregulation of nicotinic and to be associated with disorders such as schizophrenia, autism, and cancer. Beta3 subunit is depleted in the striatum of Parkinson's disease patients. Rare variants in CHRNB3 are also implicated in risk for alcohol and cocaine dependence and independently associated with bipolar disorder. Human alpha6beta2beta3* (* indicating possible additional assembly partners) nAChRs on dopaminergic neurons are important targets for drugs to treat nicotine addiction and Parkinson's disease; (alpha6beta2)(alpha4beta2)beta3 nAChR is essential for addiction to nicotine and a target for drug development for smoking cessation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSLWIPDIVLFDNADGRFEGA-STKT 150
Cdd:cd19026    1 IKVLFGLKISQLVDVDEKNQLMTTNVWLKQEWMDHKLRWNPEDYGGITSIRVPSESLWLPDIVLFENADGRFEGSlMTKA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 151 VVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILEDQDVDRTDFFDNGEWEIMSAMGSKGNR 230
Cdd:cd19026   81 IVKYNGTVTWTPPASYKSSCTMDVTFFPFDRQNCSMKFGSWTYDGNMVDLILIDENVDRKDFFDNGEWEILNAKGMKGNR 160

                        170
                 ....*....|....*....
gi 158534079 231 TDSCCWYPYITYSFVIKRL 249
Cdd:cd19026  161 KDGLYSYPFITYSFVLRRL 179

extracellular domain of nicotinic acetylcholine receptor; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits, and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSLWIPDIVLFDNADGRFEGA-STKT 150
Cdd:cd18997    1 VNVTFGLTLRQIIDVDEKNQVLTTNVWLRQEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYNNADGDFDSSyKTNV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 151 VVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILEDQDVDRTDFFDNGEWEIMSAMGSKGNR 230
Cdd:cd18997   81 IVYSDGTVTWLPPAIFKSSCKIDVTYFPFDEQNCTLKFGSWTYDGSELDLQLKSDTVDLSDYIENGEWDLLGAPAKRNVV 160

                        170       180
                 ....*....|....*....|
gi 158534079 231 TDSCC--WYPYITYSFVIKR 248
Cdd:cd18997  161 KYSCCpePYPDVTFTIHIRR 180

extracellular domain of nicotinic acetylcholine receptor subunit alpha-like found in protostomia; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha-like in organisms that include arthropods, mollusks, annelid worms, and flat worms, and have their cholinergic system limited to the central nervous system. C. elegans genome encodes 29 acetylcholine receptor subunits, of which the levamisole-sensitive receptor (L-AChR) alpha-subunits, UNC-38, UNC-63, and LEV-8, included in this subfamily, form heteromers with the two non-alpha (also known as beta-like) subunits, UNC-29 and LEV-1. This receptor functions as the main excitatory postsynaptic receptor at neuromuscular junctions, indicating that many are expressed in neurons. Also included is the nicotinic alpha subunit MARA1 (Manduca ACh Receptor Alpha 1) which is expressed in Ca2+ responding neurons and contributes to the nicotinic responses in the neurons. In insects, the receptors supply fast synaptic excitatory transmission and represent a major target for several insecticides. In Drosophila, ten exclusively neuronal nAChRs have been identified, Dalpha1-Dalpha7 and Dbeta1-Dbeta3, and various combinations of these subunits and mutations are key to nAChR function. Alpha5 subunit is involved in alpha-bungarotoxin sensitivity while the alpha6 subunit is essential for the insecticidal effect of spinosad. nAChR agonists acetylcholine, nicotine, and neonicotinoids stimulate dopamine release in Drosophila larval ventral nerve cord and mutations in nAChR subunits affect how insecticides stimulate dopamine release.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  50 LFRDLFEDYERWVRP-VEHLSDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSL 128
Cdd:cd19031    5 LYDDLLSNYNYNRRPrVTNDSDTLTVKLGLKLSQLIDVDEKNQIMTTNVWLEQEWYDYKLVWDPAEYGGVEMLYVPSEDI 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 129 WIPDIVLFDNADGRFE-GASTKTVVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILEDQD- 206
Cdd:cd19031   85 WLPDIVLYNNADGNYEvTLMTKATLHYNGTVRWEPPAIYKSSCEIDVEYFPFDEQTCFMKFGSWTYDGFEVDLRHVDQKy 164

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 158534079 207 ----------VDRTDFFDNGEWEIMSAMGSKGNRTDSCCWYPY--ITYSFVIKRLPLF 252
Cdd:cd19031  165 gsedevidvgIDLSEFYPSVEWDLLEVPARRNEKYYPCCDEPYpdITFNITLRRKTLF 222

extracellular domain of nicotinic acetylcholine receptor subunit beta-like found in protostomia; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta-like in organisms that include arthropods, mollusks, annelid worms, and flat worms, and have their cholinergic system limited to the central nervous system. C. elegans genome encodes 29 acetylcholine receptor subunits, of which the levamisole-sensitive receptor alpha-subunits (L-AChR), UNC-38, UNC-63, and LEV-8, form heteromers with the two non-alpha (also known as beta-like) subunits, UNC-29 and LEV-1 found in this subfamily. This receptor functions as the main excitatory postsynaptic receptor at neuromuscular junctions, indicating that many are expressed in neurons. In insects, the receptors supply fast synaptic excitatory transmission and represent a major target for several insecticides. In Drosophila, ten exclusively neuronal nAChR subunits have been identified, Dalpha1-Dalpha7 and Dbeta1-Dbeta3, and various combinations of these subunits and mutations are key to nAChR function. Dbeta1 subunits in dopaminergic neurons play a role in acute locomotor hyperactivity caused by nicotine in male Drosophila. Mutations of Dbeta2 or Dalpha1 nAChR subunits in Drosophila strains have significantly lower neonicotinoid-stimulated release, but no changes in nicotine-stimulated release; they are highly resistant to the neonicotinoids nitenpyram and imidacloprid. This family also includes a novel nAChR found in Aplysia bag cell neurons (neuroendocrine cells that control reproduction) which is a cholinergic ionotropic receptor that is both, nicotine insensitive and acetylcholine sensitive.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  47 EDSLFRDLFEDYERWVRPVEHLSDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSD 126
Cdd:cd19032    2 EERLVRDLFRGYNYLIRPVRNMSEPVEVNFGLALIQLINVDEKNQIMKTNVWLTMYWNDYQLKWDPADYGGIKVIRVPPD 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 127 SLWIPDIVLFDNADGRFEgASTKT--VVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQV--DIIL 202
Cdd:cd19032   82 KVWKPDIVLFNNADGNYE-VSYKSnvLIYSTGEVLWVPPAIYKSSCTIDVEYFPFDQQECEMKFGSWTFNGDEVslDLYN 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 158534079 203 EDQDVDRTDFFDNGEWEIMSAMGSKGNRTDSCCWYPYITYSFVIKR 248
Cdd:cd19032  161 NKKFVDLSDYWKSGTWDIIDVPGQLVNKDDAGPTETDIIFKIKIRR 206

Neurotransmitter-gated ion-channel transmembrane region; This family includes the four transmembrane helices that form the ion channel.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  257 LIIPCIGLSFLTVVVFYLPSNE-GEKISLCTSVLVSLTVFLLVIEEIIPSSSKVIPLIGEYLVFTMIFVTLSIMVTVFAI 335
Cdd:pfam02932   1 LIIPCVLISFLSWLVFWLPADAvGEKVTLGITVLLTMTVFLLLIRESLPKTSYVVPLIGKYLLFCMVFVFLSLVETVFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  336 NIHHRSSSTHNaMAPWVRKIFLHKLPKLLCMR---------------SHADRYFT------------------QREEAES 382
Cdd:pfam02932  81 NVHHRSPSTHK-MPPWVRKIFLEKLPRLLGMKrppeappppaspgygSKAEEYILrkprselpfekqserhglGRETTCS 159

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 158534079  383 GAGPKSRNT---------LEAALDCIRYITRHVVKENDVREVVEDWKFIAQVLDRMFLWTFLLVSIIGTLGLF 446
Cdd:pfam02932 160 YGCSLGNGSsqprelspeLKKAVEGVNFIAKHLRSQDEYISVKEDWKYVAMVIDRLSRWIFPIAFVLGTLGYF 232

extracellular domain of neuronal acetylcholine receptor subunit alpha 4 (CHRNA4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 4 (alpha4), encoded by the CHRNA4 gene. Alpha4 forms a functional nAChR by interacting with either nAChR beta2 or beta4 subunits. Alpha4beta2, the major heteropentameric nAChR in the brain, exists in two isoforms, (alpha4)3(beta2)2 and (alpha4)2(beta2)3, with the latter believed to constitute the majority of alpha4beta2 nAChR in the cortex. Both isoforms contain two canonical alpha4:beta2 ACh-binding sites with either low or high ACh sensitivity. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene (CHRNA4) cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene may provide protection against nicotine addiction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSLWIPDIVLFDNADGRFEGAS-TKT 150
Cdd:cd19017    1 VLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWRPDIVLYNNADGDFAVTHlTKA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 151 VVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILEDQDVDRTDFFDNGEWEIMSAMGSKGNR 230
Cdd:cd19017   81 HLFHDGRVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFGSWTYDKAKIDLVSMHSRVDQLDFWESGEWVIVDAVGTYNTR 160

                        170       180
                 ....*....|....*....|.
gi 158534079 231 TDSCCW--YPYITYSFVIKRL 249
Cdd:cd19017  161 KYECCAeiYPDITYAFIIRRL 181

nicotinic acetylcholine receptor (nAChR) subunit extracellular domain in molluscs and annelids; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit found in molluscs, including several Lymnaea nAChRs, and annelids that are mostly uncharacterized. To date, 12 Lymnaea nAChRs have been identified which can be subdivided in two subtypes according to the residues that may be contributing to the selectivity of ion conductance. Phylogenetic analysis of the nAChR gene sequences suggests that anionic nAChRs in molluscs probably evolved from cationic ancestors through amino acid substitutions in the ion channel pore which is a mechanism different from acetylcholine-gated channels in other invertebrates.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSLWIPDIVLFDNADGRF-EGASTKT 150
Cdd:cd19033    1 VTVEFGLQLIQILDLDENNQVLTTNVWSRYRWTDYHLRWNPEDYGGVTHVRIPPDKIWTPDIKLYNYADERLeERREAMV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 151 VVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIIL--EDQDVDRTDFFDNGEWEIMSAMGSKG 228
Cdd:cd19033   81 VVYSTGTVLWMPQAIYKSTCEIDIKYFPFDTQTCYLKFGSWTYDGTRLDITFydNEEEIDLTDYIESNEWEILAYPAVKN 160

                        170       180
                 ....*....|....*....|..
gi 158534079 229 NRTDSCCWYPY--ITYSFVIKR 248
Cdd:cd19033  161 VKYYPCCPEPYpdLTFFLVIKR 182

extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (beta4), encoded by the CHRNB4 gene and ubiquitously expressed on lung epithelial cells. The cluster of human neuronal nicotinic receptor gene CHRNA5-CHRNA3-CHRNB4 is related to drug-related behaviors and the development of lung cancer. One of the most broadly expressed subtype is the alpha-3 beta-4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or pre-synaptic excitation, mainly by increased Na+ and K+ permeability. Beta4 forms heteromeric nAchRs to modulate receptor affinity for nicotine, but the exact pentameric stochiometry of alpha3beta4 receptor is not known; functional assemblies with varying subunit stoichiometries are possible.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSLWIPDIVLFDNADGRFE-GASTKT 150
Cdd:cd19027    1 VSIKLQLSLAQLISVNEREQIMTTNVWLNQEWTDYRLTWNPSDYEGINKLRIPAKHIWLPDIVLYNNADGTYEvSVYTNA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 151 VVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILEDQDVDRTDFFDNGEWEIMSAMGSKG-N 229
Cdd:cd19027   81 IVQNNGSVAWLPPAIYKSACKIEVKHFPFDQQNCTLKFRSWTYDHTEIDMVLKTPTASMDDFTPSGEWDIVALPGRRTvN 160

                        170
                 ....*....|....*....
gi 158534079 230 RTDSCcwYPYITYSFVIKR 248
Cdd:cd19027  161 PLDPT--YVDVTYDFIIKR 177

extracellular domain (LBD) of cationic Cys-loop neurotransmitter-gated ion channels; This superfamily contains the extracellular domain (ECD) of cationic Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), and zinc-activated ligand-gated ion channel (ZAC) receptor. These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. ZAC forms an ion channel gated by Zn2+, Cu2+, and H+ and is non-selectively permeable to monovalent cations. However, the role of ZAC in Zn2+, Cu2+, and H+ signaling require is as yet unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSLWIPDIVLFDNADGR--FEGASTK 149
Cdd:cd18989    1 VNVNVSFSLYSILDLDEVEQTLTLSGWLTLTWTDERLTWNPSDYGGITSIVVPSSEIWTPDIVLYNSVDSLdlLGDSNTL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 150 TVVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILEDQDVDRTDFFDNGEWEIMSAMGSKGN 229
Cdd:cd18989   81 VRVSSDGTVTWVPPGVLTTSCDIDVTYFPFDTQTCSLRFGSWSYTTDEINLTPSSNGVDLEDYEENGEWELLSTSVSREE 160

                        170
                 ....*....|....*....
gi 158534079 230 RTDSCCWYPYITYSFVIKR 248
Cdd:cd18989  161 DKYCNETYSELTFTITLKR 179

extracellular domain of neuronal acetylcholine receptor subunit alpha 10 (CHRNA10); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 10 (alpha10), encoded by the CHRNA10 gene. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea as well as in keratinocytes, the pituitary gland, B-cells, and T-cells. Unlike alpha9 nAChR subunits, alpha10 subunits do not generate functional channels when expressed heterologously, suggesting that alpha10 might serve as a structural subunit, much like a beta subunit of heteromeric receptors, providing only complementary components to the agonist binding site. Mammalian alpha10 subunits can form functional heteromeric alpha9alpha10 receptors, an atypical heteromeric receptor since it is composed only of alpha subunits compared to nAChRs typically assembled from alpha and beta subunits. A stoichiometry of (alpha9)2(alpha10)3 has been determined for the rat recombinant receptor. The alpha9alpha10 nAChR is an important therapeutic target for pain; selective block of alpha9alpha10 nicotinic acetylcholine receptors by the conotoxin RgIA has been shown to be analgesic in an animal model of nerve injury pain, and accelerates recovery of nerve function after injury, possibly through immune/inflammatory-mediated mechanisms.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSLWIPDIVLFDNADGRFEGA-STKT 150
Cdd:cd19023    1 LNVTLQITLSQIIDMDERNQILTAYLWIRQVWLDAYLAWNKEAYDGLDTIRIPSSYVWRPDIVLYNNADDRFTGSmETNV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 151 VVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIILEDQDVDRTDFFDNGEWEIMSAMGSKGNR 230
Cdd:cd19023   81 VIRSDGQIMWDSPAITKSSCKVDVSFFPFDGQQCRLTFGSWTYNGNQIDILNLLDTGDLTDFVENVEWEVLGMPAKRNVI 160

                        170       180
                 ....*....|....*....|
gi 158534079 231 TDSCCWYPY--ITYSFVIKR 248
Cdd:cd19023  161 TYGCCSEPYpdVTYTLLLKR 180

extracellular domain of nicotinic acetylcholine receptor subunit gamma (CHRNG); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit gamma (gamma), encoded by the CHRNG gene expressed during early fetal development, and replaced by the epsilon subunit in the adult. The gamma subunit forms a heteropentamer with (alpha1)2, beta, and delta and plays a role in neuromuscular organogenesis and ligand binding. Disruption of gamma subunit expression prevents the correct localization of the receptor in cell membranes. Mutations in CHRNG may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome (MPS), a condition characterized by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis. Muscle-type acetylcholine receptor is the major antigen in the autoimmune disease myasthenia gravis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079  70 DKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKIIRVPSDSLWIPDIVLFDNADGRFEGA-ST 148
Cdd:cd19029    1 DVVDVTLKLTLTNLISLNEKEEALTTNVWIEIQWNDYRLRWNPSEYEGIWVLRVPSTMVWLPDIVLENNIDGQFEVAyYA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 149 KTVVRYNGTVTWTQPANYKSSCTIDVTFFPFDLQNCSMKFGSWTYDGSQVDIIL--------EDQDVDRTDFFDNGEWEI 220
Cdd:cd19029   81 NVLVYPDGSMYWLPPAIYRSTCPIEVTYFPFDWQNCSLVFQSQTYSANEINLQLsveegttiEWIDIDPEAFTENGEWAI 160

                 .
gi 158534079 221 M 221
Cdd:cd19029  161 R 161

transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 251 LFYTLFLIIPCIGLSFLTVVVFYLPSNEGEKISLCTSVLVSLTVFLLVIEEIIPSSSKVIPLIGEYLVFTMIFVTLSIMV 330
Cdd:cd19064    1 LFYTVNLIIPCVLISFLTVLVFYLPADSGEKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSIIV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158534079 331 TVFAINIHHRsssthnamapwvrkiflhklpkllcmrshadryftqreeaesgagpksrntleaaldciryitrhvvken 410
Cdd:cd19064   81 TVIVLNVHHR---------------------------------------------------------------------- 90

                        170       180       190
                 ....*....|....*....|....*....|....*..
gi 158534079 411 dvrevvedwkfiaqVLDRMFLWTFLLVSIIGTLGLFV 447
Cdd:cd19064   91 --------------VIDRLFLWIFLLVCVIGTLGIFL 113